Following absorption or systemic administration into the bloodstream, a drug distributes into interstitial and intracellular fluids depending on the particular physicochemical properties of the drug. Cardiac output, regional blood flow, capillary permeability, and tissue volume determine the rate of delivery and potential amount of drug distributed into tissues. Initially, liver, kidney, brain, and other well-perfused organs receive most of the drug, whereas delivery to muscle, most viscera, skin, and fat is slower. This second distribution phase may require minutes to several hours before the concentration of drug in tissue is in equilibrium with that in blood. The second phase also involves a far larger fraction of body mass than does the initial phase and generally accounts for most of the extravascularly distributed drug. With exceptions such as the brain, diffusion of drug into the interstitial fluid occurs rapidly. Thus, tissue distribution is determined by the partitioning of drug between blood and the particular tissue.
PLASMA PROTEINS Many drugs circulate in the bloodstream reversibly bound to plasma proteins. Albumin is a major carrier for acidic drugs; a^-acid glycoprotein binds basic drugs. Nonspecific binding to other plasma proteins generally occurs to a much smaller extent. In addition, certain drugs may bind to proteins that function as specific hormone carrier proteins, such as the binding of thyroid hormone to thyroxin-binding globulin.
The fraction of total drug in plasma that is bound is determined by the drug concentration, the affinity of binding sites for the drug, and the number of binding sites. For most drugs, the therapeutic range of plasma concentrations is limited; thus the extent of binding and the unbound fraction are relatively constant. The extent of plasma protein binding may be affected by disease-related factors (e.g., hypoalbuminemia). Conditions resulting in the acute-phase reaction response (e.g., cancer, arthritis, myocardial infarction, and Crohn's disease) lead to elevated levels of aj-acid glycoprotein and enhanced binding of basic drugs.
Many drugs with similar physicochemical characteristics can compete with each other and with endogenous substances for protein binding. Drug toxicities based on competition between drugs for binding sites is not of clinical concern for most therapeutic agents. Steady-state unbound concentrations of drug will change significantly only when either input (dosing rate) or clearance of unbound drug is changed [see Equation (1—2)]. Thus, steady-state unbound concentrations are independent of the extent of protein binding. However, for narrow-therapeutic-index drugs, a transient change in unbound concentrations occurring immediately following the dose of a competing drug could be of concern, such as with the anticoagulant warfarin.
Importantly, binding of a drug to plasma proteins limits its concentration in tissues and at its site of action because only unbound drug is in equilibrium across membranes. Accordingly, after distribution equilibrium is achieved, the concentration of active, unbound drug in intracellular water is the same as that in plasma except when carrier-mediated transport is involved. Binding of a drug to plasma protein also limits the drug's glomerular filtration because this process does not immediately change the concentration of free drug in the plasma (water is also filtered). Drug transport and metabolism also are limited by binding to plasma proteins, except when these are especially efficient, and drug clearance, calculated on the basis of unbound drug, exceeds organ plasma flow.
TISSUE BINDING Many drugs accumulate in tissues at higher concentrations than those in the extracellular fluids and blood. Tissue binding of drugs usually occurs with cellular constituents such as proteins, phospholipids, or nuclear proteins and generally is reversible. A large fraction of drug in the body may be bound in this fashion and serve as a reservoir that prolongs drug action in that same tissue or at a distant site reached through the circulation. Such tissue binding and accumulation also can produce local toxicity.
Many lipid-soluble drugs are stored by physical solution in the neutral fat. In obese persons, the fat content of the body may be as high as 50%, and even in lean individuals it constitutes 10% of body weight; hence, fat may serve as a reservoir for lipid-soluble drugs. Fat is a rather stable reservoir because it has a relatively low blood flow.
REDISTRIBUTION Termination of drug effect after withdrawal of a drug may result from redistribution of the drug from its site of action into other tissues or sites. Redistribution is a factor primarily when a highly lipid-soluble drug that acts on the brain or cardiovascular system is administered rapidly by intravenous injection or by inhalation. The highly lipid-soluble drug reaches its maximal concentration in brain within seconds of its intravenous injection; the plasma concentration then falls as the drug diffuses into other tissues, such as muscle. The concentration of the drug in brain follows that of the plasma because there is little binding of the drug to brain constituents. Thus, the onset of action is rapid, and its termination is rapid, related directly to the concentration of drug in the brain.
CENTRAL NERVOUS SYSTEM AND CEREBROSPINAL FLUID Brain capillary endothelial cells have continuous tight junctions; therefore, drug penetration into the brain depends on transcellular rather than paracellular transport. The unique characteristics of brain capillary endothelial cells and pericapillary glial cells constitute the blood-brain barrier. At the choroid plexus, a similar blood-CSF barrier is present based on epithelial tight junctions. The lipid solubility of the nonionized and unbound species of a drug is therefore an important determinant of its uptake by the brain; the more lipophilic a drug is, the more likely it is to cross the blood-brain barrier. Drugs may penetrate into the CNS by specific uptake transporters (Chapter 2).
PLACENTAL TRANSFER OF DRUGS The transfer of drugs across the placenta is of critical importance because drugs may cause anomalies in the developing fetus. Lipid solubility, extent of plasma binding, and degree of ionization of weak acids and bases are important general determinants in drug transfer across the placenta. The fetal plasma is slightly more acidic than that of the mother (pH 7.0-7.2 vs. 7.4), so that ion trapping of basic drugs occurs. The view that the placenta is an absolute barrier to drugs is, however, completely inaccurate, in part because a number of influx transporters are also present. The fetus is to some extent exposed to all drugs taken by the mother.
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